scholarly journals Mixed chimerism

2001 ◽  
Vol 356 (1409) ◽  
pp. 707-726 ◽  
Author(s):  
Megan Sykes ◽  
David H. Sachs
Keyword(s):  
Lymphocyte Subsets ◽  
Tolerance Induction ◽  
Mixed Chimerism ◽  
Large Animal ◽  
Rodent Models ◽  
Cell Type ◽  
Potential Toxicity ◽  
Large Animal Models ◽  
Conditioning Regimens ◽  
Made In

Induction of mixed chimerism has the potential to overcome the current limitations of transplantation, namely chronic rejection, complications of immunosuppressive therapy and the need for xenografts to overcome the current shortage of allogeneic organs. Successful achievement of mixed chimerism had been shown to tolerize T cells, B cells and possibly natural killer cells, the lymphocyte subsets that pose major barriers to allogeneic and xenogeneic transplants. Current understanding of the mechanisms involved in tolerization of each cell type is reviewed. Considerable advances have been made in reducing the potential toxicity of conditioning regimens required for the induction of mixed chimerism in rodent models, and translation of these strategies to large animal models and in a patient are important advances toward more widespread clinical application of the mixed chimerism approach for tolerance induction.

scholarly journals Large Animal Models of Vascularized Composite Allotransplantation: A Review of Immune Strategies to Improve Allograft Outcomes

2021 ◽  
Vol 12 ◽  
Author(s):  
Abraham J. Matar ◽  
Rebecca L. Crepeau ◽  
Gerhard S. Mundinger ◽  
Curtis L. Cetrulo ◽  
Radbeh Torabi
Keyword(s):  
Animal Models ◽  
Ex Vivo ◽  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Large Animal ◽  
Solid Organ ◽  
Large Animal Models ◽  
Large Animals ◽  
And Function ◽  
Made In

Over the past twenty years, significant technical strides have been made in the area of vascularized composite tissue allotransplantation (VCA). As in solid organ transplantation, the allogeneic immune response remains a significant barrier to long-term VCA survival and function. Strategies to overcome acute and chronic rejection, minimize immunosuppression and prolong VCA survival have important clinical implications. Historically, large animals have provided a valuable model for testing the clinical translatability of immune modulating approaches in transplantation, including tolerance induction, co-stimulation blockade, cellular therapies, and ex vivo perfusion. Recently, significant advancements have been made in these arenas utilizing large animal VCA models. In this comprehensive review, we highlight recent immune strategies undertaken to improve VCA outcomes with a focus on relevant preclinical large animal models.

scholarly journals Large Animal Models of Huntington’s Disease: What We Have Learned and Where We Need to Go Next

2020 ◽  
Vol 9 (3) ◽  
pp. 201-216
Author(s):  
David Howland ◽  
Zdenka Ellederova ◽  
Neil Aronin ◽  
Deborah Fernau ◽  
Jill Gallagher ◽  
...  
Keyword(s):  
Animal Models ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Single Species ◽  
Research Community ◽  
Response To Treatment ◽  
Large Animal ◽  
Rodent Models ◽  
Large Animal Models ◽  
Translational Studies

Genetically modified rodent models of Huntington’s disease (HD) have been especially valuable to our understanding of HD pathology and the mechanisms by which the mutant HTT gene alters physiology. However, due to inherent differences in genetics, neuroanatomy, neurocircuitry and neurophysiology, animal models do not always faithfully or fully recapitulate human disease features or adequately predict a clinical response to treatment. Therefore, conducting translational studies of candidate HD therapeutics only in a single species (i.e. mouse disease models) may not be sufficient. Large animal models of HD have been shown to be valuable to the HD research community and the expectation is that the need for translational studies that span rodent and large animal models will grow. Here, we review the large animal models of HD that have been created to date, with specific commentary on differences between the models, the strengths and disadvantages of each, and how we can advance useful models to study disease pathophysiology, biomarker development and evaluation of promising therapeutics.

scholarly journals Chimerism-Based Experimental Models for Tolerance Induction in Vascularized Composite Allografts: Cleveland Clinic Research Experience

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Maria Siemionow ◽  
Aleksandra Klimczak
Keyword(s):  
Current Knowledge ◽  
Cleveland Clinic ◽  
Experimental Studies ◽  
Tolerance Induction ◽  
Experimental Models ◽  
Successful Outcome ◽  
Large Animal ◽  
Research Experience ◽  
Widespread Application ◽  
Large Animal Models

The preclinical experimental models of vascularized composite allografts (VCAs) have been rapidly developed for the assessment of immunomodulatory protocols for clinical application. Recently, researchers have focused on immunomodulatory protocols which overcome the immunologic barrier between the allogeneic donor and recipient and may lead to tolerance induction. In order to test the feasibility of chimerism induction, experimental VCAs have been performed in different models including rodents, large animals, and nonhuman primates. These models differ in the complexity of transplanted tissue and in their responses to immunomodulatory protocols. In most applications, VCA contains multiple-tissue components; however, each individual component of CTA possesses unique immunologic characteristics that ultimately contribute to the chimerism induction and successful outcome of the VCA. Heterogenic character and complexity of tissue components in different VCA models determine the quality and robustness of donor-specific chimerism. As introduced in experimental studies, variable immunomodulatory options have been studied to achieve tolerance to VCA in rodents and large animal models allowing for widespread application in clinic. In this paper, based on our own experience, we have analyzed the current knowledge of tolerance-inducing strategies via chimerism induction in VCA experimental models in the context of immunomodulatory protocols and VCA complexity and their relevance and applicability to clinical practice.

scholarly journals Characterisation of the horse transcriptome from immunologically active tissues

2014 ◽  
Author(s):  
Joanna Moreton ◽  
Sunir Malla ◽  
Aziz Aboobaker ◽  
Rachael Tarlinton ◽  
Richard D Emes
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Animal Models ◽  
Genome Annotation ◽  
Large Animal ◽  
Suitable Model ◽  
Rodent Models ◽  
Large Animal Models ◽  
Human Disorders ◽  
Novel Isoforms

The immune system of the horse has not been well studied, despite the fact that the horse displays several features such as sensitivity to bacterial lipopolysaccharide that make them in many ways a more suitable model of some human disorders than the current rodent models. The difficulty of working with large animal models has however limited characterisation of gene expression in the horse immune system with current annotations for the equine genome restricted to predictions from other mammals and the few described horse proteins. This paper outlines sequencing of 184 million transcriptome short reads from immunologically active tissues of three horses including the genome reference “Twilight”. In a comparison with the Ensembl horse genome annotation, we found 8,763 potentially novel isoforms.

scholarly journals Porcine Models of Accelerated Coronary Atherosclerosis: Role of Diabetes Mellitus and Hypercholesterolemia

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Damir Hamamdzic ◽  
Robert L. Wilensky
Keyword(s):  
Animal Models ◽  
Coronary Atherosclerosis ◽  
Pig Model ◽  
Large Animal ◽  
Rodent Models ◽  
Miniature Pig ◽  
Therapeutic Approaches ◽  
Large Animal Models ◽  
Atherosclerotic Lesions

Animal models of atherosclerosis have proven to be an invaluable asset in understanding the pathogenesis of the disease. However, large animal models may be needed in order to assess novel therapeutic approaches to the treatment of atherosclerosis. Porcine models of coronary and peripheral atherosclerosis offer several advantages over rodent models, including similar anatomical size to humans, as well as genetic expression and development of high-risk atherosclerotic lesions which are similar to humans. Here we review the four models of porcine atherosclerosis, including the diabetic/hypercholesterolemic model, Rapacz-familial hypercholesterolemia pig, the (PCSK9) gain-of-function mutant pig model, and the Ossabaw miniature pig model of metabolic syndrome. All four models reliably represent features of human vascular disease.

scholarly journals Characterisation of the horse transcriptome from immunologically active tissues

2014 ◽  
Author(s):  
Joanna Moreton ◽  
Sunir Malla ◽  
Aziz Aboobaker ◽  
Rachael Tarlinton ◽  
Richard D Emes
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Animal Models ◽  
Genome Annotation ◽  
Large Animal ◽  
Suitable Model ◽  
Rodent Models ◽  
Large Animal Models ◽  
Human Disorders ◽  
Novel Isoforms

The immune system of the horse has not been well studied, despite the fact that the horse displays several features such as sensitivity to bacterial lipopolysaccharide that make them in many ways a more suitable model of some human disorders than the current rodent models. The difficulty of working with large animal models has however limited characterisation of gene expression in the horse immune system with current annotations for the equine genome restricted to predictions from other mammals and the few described horse proteins. This paper outlines sequencing of 184 million transcriptome short reads from immunologically active tissues of three horses including the genome reference “Twilight”. In a comparison with the Ensembl horse genome annotation, we found 8,763 potentially novel isoforms.

scholarly journals Clinical and preclinical tolerance protocols for vascularized composite allograft transplantation

2021 ◽  
Vol 48 (6) ◽  
pp. 703-713
Author(s):  
Jerry Huanda Yang ◽  
Ariel C. Johnson ◽  
Salih Colakoglu ◽  
Christene A. Huang ◽  
David Woodbridge Mathes
Keyword(s):  
Radiation Treatment ◽  
Immunosuppressive Treatment ◽  
Tolerance Induction ◽  
Human Leukocyte ◽  
Donor Cell ◽  
Large Animal ◽  
Valuable Insight ◽  
Widespread Application ◽  
Large Animal Models ◽  
Vascularized Composite Allograft

The field of vascularized composite allografts (VCAs) has undergone significant advancement in recent decades, and VCAs are increasingly common and accepted in the clinical setting, bringing hope of functional recovery to patients with debilitating injuries. A major obstacle facing the widespread application of VCAs is the side effect profile associated with the current immunosuppressive regimen, which can cause a wide array of complications such as infection, malignancy, and even death. Significant concerns remain regarding whether the treatment outweighs the risk. The potential solution to this dilemma would be achieving VCA tolerance, which would allow recipients to receive allografts without significant immunosuppression and its sequelae. Promising tolerance protocols are being studied in kidney transplantation; four major trials have attempted to withdraw immunosuppressive treatment with various successes. The common theme in all four trials is the use of radiation treatment and donor cell transplantation. The knowledge gained from these trials can provide valuable insight into the development of a VCA tolerance protocol. Despite similarities, VCAs present additional barriers compared to kidney allografts regarding tolerance induction. VCA donors are likely to be deceased, which limits the time for significant pre-conditioning. VCA donors are also more likely to be human leukocyte antigen–mismatched, which means that tolerance must be induced across major immunological barriers. This review also explores adjunct therapies studied in large animal models that could be the missing element in establishing a safe and stable tolerance induction method.

scholarly journals Molecular Mechanisms of Fetal Tendon Regeneration Versus Adult Fibrous Repair

2021 ◽  
Vol 22 (11) ◽  
pp. 5619
Author(s):  
Iris Ribitsch ◽  
Andrea Bileck ◽  
Alexander D. Aldoshin ◽  
Maciej M. Kańduła ◽  
Rupert L. Mayer ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Unmet Need ◽  
Tendon Healing ◽  
Tendon Injury ◽  
Inflammatory Factors ◽  
Large Animal ◽  
Post Injury ◽  
Tendon Regeneration ◽  
Large Animal Models

Tendinopathies are painful, disabling conditions that afflict 25% of the adult human population. Filling an unmet need for realistic large-animal models, we here present an ovine model of tendon injury for the comparative study of adult scarring repair and fetal regeneration. Complete regeneration of the fetal tendon within 28 days is demonstrated, while adult tendon defects remained macroscopically and histologically evident five months post-injury. In addition to a comprehensive histological assessment, proteome analyses of secretomes were performed. Confirming histological data, a specific and pronounced inflammation accompanied by activation of neutrophils in adult tendon defects was observed, corroborated by the significant up-regulation of pro-inflammatory factors, neutrophil attracting chemokines, the release of potentially tissue-damaging antimicrobial and extracellular matrix-degrading enzymes, and a response to oxidative stress. In contrast, secreted proteins of injured fetal tendons included proteins initiating the resolution of inflammation or promoting functional extracellular matrix production. These results demonstrate the power and relevance of our novel ovine fetal tendon regeneration model, which thus promises to accelerate research in the field. First insights from the model already support our molecular understanding of successful fetal tendon healing processes and may guide improved therapeutic strategies.

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